The three main chondroitin sulfate proteoglycans (CSPGs) of the arterial wall are versican and two small leucine rich proteoglycans (SLRPs), decorin & biglycan. We have performed the first study of atherogenesis in a CSPG knock-out, the decorin null mouse, which unexpectedly exhibited a substantial increase in lesions. The focus of this Project is to understand the effects of the decorin and biglycan CSPGs in atherogenesis on a molecular level, by broadly examining known functions and functional domains. Our central hypothesis is that the primary role of decorin in atherogenesis is not as a retentive molecule, but instead as a regulatory molecule that reduces the ability of locally synthesized biglycan and versican to retain lipoproteins. In contrast, we hypothesize that biglycan is primarily a retentive molecule, leading to pro-atherogenic effects. The proposed approaches follow the major theme of the SCOR, namely, the use of genetic manipulations of mice to investigate roles of specific arterial-wall molecules in atherogenesis. This Project involves extensive collaborations with Project 1, the Pathology Core, the Gene Expression Core, and the Clinical Core, and there is a shared theme with Project 8. Aim 1: Effects of decorin on atherogenic processes within the arterial wall in vivo. Four regulatory functions of decorin have been reported, each of which could be considered anti-atherogenic, particularly the inhibition of TGFbeta action. We will assess the effect of the decorin KO on arterial proteoglycan structure and lipoprotein binding, which are known to be altered by TGFbeta; and use real-time PCR and a broader gene chip survey to quantitate mRNAs, such as biglycan, that are affected by regulatory actions of decorin. Aim 2: Novel mouse models to investigate the role of decorin in atherogenesis. We will examine biglycan/decorin double KOs, to determine if overexpression of biglycan contributes to atherogenesis in decorin deficient mice. To determine the roles of the decorin domains for CS attachment and high-affinity TGFbeta binding, we propose to engineer mice lacking each of these domains, then quantitate development of atherosclerosis. Aim 3: A comprehensive search for decorin alleles that affect human vascular disease. We will perform a comprehensive search for common and rare human decorin polymorphisms. We will then screen human cohorts for the relationship of these decorin polymorphisms to cardiovascular disease. Overall, our proposed studies will establish the molecular roles of specific arterial-wall CSPGs and their, specific functional domains in atherogenesis in vivo in mice, with extensions to the human disease.